Toxicity from ethanol and related stressors is a major etiologic factor linked to birth defects, cancer, cirrhosis and other important diseases. Apoptosis is well established as a critical pathologic feature contributing to ethanol-induced tissue injury but effectors that couple exposure of this agent to cell death are not known. In order to understand how alcohol instigates and/or exacerbates human disease, it is necessary to identify the signaling mechanisms that elicit apoptogenic responses to this stimulus. Understanding fundamental pathways that support apoptogenic responses to alcohol in vivo is an organizing goal of this project. Our central hypothesis predicts that core effectors of alcohol toxicity are universally shared across the animal kingdom and likely define authentic targets for therapeutic intervention. To initiate comprehensive studies, we established robust models of ethanol-induced toxicity in human, zebrafish and Drosophila systems. Our strategy emphasizes a functional approach, from widely divergent systems, to identify conserved pathways required for alcohol-induced cell death. Aims 1 and 2 leverage functional genomic screening platforms, together with robust models of alcohol-induced killing in relevant human and Drosophila cell lines, to expose commonly shared effectors of sensitivity to this stressor. In Aim 3, we interrogate these universal effectors in whole animal models of alcohol-induced tissue damage. Together, our studies will identify critical determinants that support alcohol-related pathology and could establish proof of principle for mitigating disease through the control of apoptosis. In turn, these insights will expose new opportunities for improved management of disease caused by alcohol and related stressors in humans